This application is a continuation-in-part of Faustman U.S. Ser. No. 07/575,150, filed Aug. 30, 1990. This invention relates to transplantation of tissues, e.g., islet cells, muscle cells, and whole organs, into hosts in need of such tissues, e.g., patients who have or are at risk of developing diabetes mellitus, have muscular dystrophy, or are in need of an organ transplant.
Diabetes mellitus is a prevalent degenerative disease, characterized by insulin deficiency, which prevents normal regulation of blood glucose levels, and which leads to hypergylycemia and ketoacidosis.
Insulin, a peptide hormone, promotes glucose utilization, protein synthesis, formation and storage of neutral lipids, and the growth of some cell types. Insulin is produced by the β cells within the islets of Langerhans of the pancreas. Early-onset diabetes (10-20% of cases) is caused by an auto-immune reaction that causes complete destruction of β cells. Adult-onset diabetes has a number of causes, but in most cases the β islet cells are defective in secretion of insulin.
Insulin injection therapy, usually with porcine or bovine insulin, prevents severe hyperglycemia and ketoacidosis, but fails to completely normalize blood glucose levels. While injection therapy has been quite successful, it fails to prevent the premature vascular deterioration that is now the leading cause of morbidity among diabetics. Diabetes-related vascular deterioration, which includes both microvascular degeneration and acceleration of atherosclerosis, can eventually cause renal failure, retinal deterioration, angina pectoris, myocardial infarction, peripheral neuropathy, and arteriosclerosis.
Recently, cloning of the human insulin-encoding gene has allowed large scale production of human insulin, which has begun to replace bovine insulin and procine insulin as the treatment of choice. Use of human insulin has eliminated some of the problems associated with other forms of insulin, including antibody-mediated insulin resistance and allergic reactions resulting from the slightly different structures of non-human insulins. Despite these advantages, treatment with human insulin does not prevent vascular deterioration.
Insulin delivery pumps have been developed which administer varying doses of insulin based on activity, diet, time of day, and other pre-programmed factors. While such devices improve blood sugar control, they also do not prevent vascular deterioration.
Surgical transplantation of part or all of the pancreas is thought to be potentially the best treatment for diabetes. Successful transplantation is difficult, however, because the pancreas is a fragile and complicated organ, and it is impossible for a human donor to give only a portion of it; the only practicable source is a deceased donor. Further, only a small portion of the pancreas, the β cells of the islet of Langerhans, produce insulin; the remainder of the pancreas presents a potent target for transplant rejection. Transplantation of just the islets of Langerhans is a desirable goal, as they continue to secrete appropriate amounts of insulin in response to nutritional signals even when isolated from the rest of the pancreas.
A major problem associated with transplantation therapy as a treatment for diabetes is that current regimes require life-long administration of immunosuppressive drugs. These drugs can cause increased susceptibility to infection, renal failure, hypertension, and tumor growth.
Despite these serious complications, islet transplantation has been successfully performed in experimental animals. Successful transplantation in rodents has been shown to restore normal blood glucose regulation and prevent further vascular deterioration. The broader application of allografts and xenografts (inter-species grafts) as a therapy for diabetes depends on preventing transplant rejection. It has long been known that culturing islets prior to transplantation decreases immunogenicity and increases transplant survival (Lacy et al (1979) Science 204—312; Lafferty et al. (1975) Science 188:259). It is thought that long term culturing removes the Ia-bearing passenger lymphoid cells, which are a primary stimulus for cell-mediated immunity and graft rejection. Faustman et al. (J. Exp. Med. 151:1673, 1980) found that islet cells lack Ia antigenic determinants and express class I antigen on their surfaces. This allowed Faustman et al. (Proc. Natl. Acad. of Sci. USA 78:5156, 1981) to develop a regime that used donor-specific anti-Ia serum and complement to destroy Ia bearing lymphoid cells in islets, and allowed transplantation across a major histocompatibility barrier into non-immunosuppressed diabetic mice.